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The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder serviceAndrew J. Hughes,1,3 Susan E. Daniel,1 Yoav Ben-Shlomo2 and Andrew J. Lees1 1The United Kingdom Parkinson's Disease Society Brain Correspondence to: Professor Andrew J. Lees MD, FRCP, Research Centre, Institute of Neurology, London, Reta Lila Weston Institute of Neurological Studies, 2Department of Social Medicine, University of Bristol, Windeyer Building, 46 Cleveland Street, London W1T 4JF, Bristol, UK and 3Neurology Department, Austin and Repatriation Medical Centre, Melbourne, Australia We have reviewed the clinical and pathological diagno- diagnosis of multiple system atrophy (MSA) and pro- ses of 143 cases of parkinsonism seen by neurologists gressive supranuclear palsy (PSP) were 85.7 (30 out of associated with the movement disorders service at The 35) and 80% (16 out of 20), respectively. The sensitivity National Hospital for Neurology and Neurosurgery in for IPD was 91.1%, due to seven false-negative cases, London who came to neuropathological examination at with 72 of the 79 pathologically established cases being the United Kingdom Parkinson's Disease Society Brain diagnosed in life. For MSA, the sensitivity was 88.2% Research Centre, over a 10-year period between 1990 (30 out of 34), and for PSP it was 84.2% (16 out of 19).
and the end of 1999. Seventy-three (47 male, 26 female) The diagnostic accuracy for IPD, MSA and PSP was cases were diagnosed as having idiopathic Parkinson's higher than most previous prospective clinicopathologi- disease (IPD) and 70 (42 male, 28 female) as having cal series and studies using the retrospective application another parkinsonian syndrome. The positive predictive of clinical diagnostic criteria. The seven false-negative value of the clinical diagnosis for the whole group was cases of IPD suggest a broader clinical picture of dis- 85.3%, with 122 cases correctly clinically diagnosed.
ease than previously thought acceptable. This study The positive predictive value of the clinical diagnosis of implies that neurologists with particular expertise in the IPD was extremely high, at 98.6% (72 out of 73), while ®eld of movement disorders may be using a method of for the other parkinsonian syndromes it was 71.4% (50 pattern recognition for diagnosis which goes beyond out of 70). The positive predictive values of a clinical that inherent in any formal set of diagnostic criteria.
Keywords: Parkinson's disease; parkinsonism; clinicopathological study; diagnostic accuracy Abbreviations: CBD = corticobasal degeneration; DLB = dementia with Lewy bodies; IPD = idiopathic Parkinson's disease; MSA = multiple system atrophy; NHNN = The National Hospital for Neurology and Neurosurgery, London; PEP = post-encephalitic parkinsonism; PSP = progressive supranuclear palsy; UKPDSBRC = The United Kingdom Parkinson's Disease Society Brain Research Centre Remarkably few detailed clinicopathological studies of originating from seven centres in four countries (Litvan et al., patients with parkinsonian disorders have been published (Hughes et al., 1993; Wenning et al., 1995; Litvan et al., Two clinicopathological studies published in the early 1996a) which has made assessment of the accuracy of clinical 1990s both found an accuracy of clinical diagnosis of IPD of diagnosis dif®cult. The largest clinicopathological series of 76% (Rajput et al., 1991; Hughes et al., 1992). A recent study patients with multiple system atrophy (MSA) and progressive in the UK, using ascertainment and methodology comparable supranuclear palsy (PSP), the two disorders most likely to with one of the earlier studies, has shown an improvement in mimic idiopathic Parkinson's disease (IPD), include only 38 this diagnostic accuracy to 90% (Hughes et al., 2001). This and 24 cases, respectively, with the latter comprising cases improvement coincides with increased awareness amongst neurologists of the pitfalls in the differential diagnosis of cases from the UKPDSBRC (Hughes et al., 1993, 2001; parkinsonian syndromes and the publication of consensus Wenning et al., 1994, 1995, 2000; Daniel et al., 1995; Litvan operational criteria for the diagnosis of IPD, MSA, PSP and et al., 1996c, 1997a, b, 1998). The clinical features of the 143 corticobasal degeneration (CBD) (Gibb and Lees, 1988; cases identi®ed were abstracted by one neurologist (A.J.H.), Litvan et al., 1996b; Gilman et al., 1999; Riley and Lang, unblinded to the pathological diagnosis, from clinical records 2000). However, there is little information available about the which included hospital, consultant and general practice case accuracy of diagnosis of other parkinsonian syndromes and notes as well as UKPDSBRC annual assessment data.
whether specialists in movement disorders are superior to Clinical features were entered on a database for subsequent general neurologists. Two clinicopathological studies have analysis. In addition to standard clinical parameters, particu- suggested that approximately one-third of patients with lar attention was paid to the initial clinical diagnosis, the pathologically proven MSA seen by specialists in movement timing of that diagnosis in relation to the initial onset of disorders carry the incorrect diagnosis at death (Wenning symptoms, the time of any change to the clinical diagnosis et al., 1995; Litvan et al., 1997a). This ®gure may be as high and the time prior to death of the last clinical assessment.
as 50% in patients diagnosed by general neurologists (Litvan Where more than one possible clinical diagnosis was listed in et al., 1997a). In PSP, available clinicopathological correla- the clinical ®les, an attempt was made to ascertain the clinical tive data would suggest that between 41 and 88% of patients diagnosis thought most likely. Only in cases where this was with pathologically proven PSP are diagnosed correctly in unclear, or where a de®nite `unclassi®able' label had been life (Daniel et al., 1995; Litvan et al., 1996a; Verny et al., used was a ®nal clinical diagnosis of `parkinsonism undetermined' recorded. For analysis of diagnostic accuracy, To assess further the accuracy of diagnosis of parkinsonian cases with a ®nal diagnosis of parkinsonism undetermined disorders, we have reviewed the clinical and pathological were classi®ed as having a parkinsonian syndrome other than diagnoses of patients seen by neurologists associated with the IPD and were considered to have an incorrect clinical movement disorders service at The National Hospital for Neurology and Neurosurgery in London (NHNN) who came The clinical diagnostic label of dementia with Lewy bodies to neuropathological examination at the United Kingdom (DLB) was problematic because of the evolution in the Parkinson's Disease Society Brain Research Centre clinical understanding of this entity and its clinicopathologi- cal de®nition over the time of the study (McKeith et al., 1996, 1999). The classi®cation of patients as having DLB at autopsy was also complicated by occasional cases with moderate numbers of cortical Lewy bodies who either had no cognitive We identi®ed 143 cases of parkinsonism seen by neurologists impairment in life or who ®rst developed cognitive dysfunc- associated with the movement disorders service at the NHNN tion after a disease course of 10 years or more. As such, cases who came to neuropathological assessment at the clinically felt to have IPD and coexistent dementia at the time UKPDSBRC from the beginning of 1990 until the end of of death were classi®ed as having a clinical diagnosis of IPD, and all cases satisfying the neuropathological criteria for IPD with or without cortical Lewy body deposition were classi®ed The cases were identi®ed from all cases referred to the UKPDSBRC over the 10-year period, by review of all case records and clinical summaries, completed at the time of Half-brains ®xed in 10% neutral formalin were examined neuropathological assessment, and by a search of the clinical using standard neuropathological techniques. Tissue for database for the names of the treating consultant neurologists paraf®n embedding was taken from the cerebral cortex, and for any record of attendance at the NHNN. The accrual striatum, mid-brain, pons, medulla and cerebellum. In the rate of 14±15 brains per year represents ~8% of patients with majority of cases, all areas of cortex (frontal, temporal, parkinsonism admitted to the hospital each year and <5% of parietal and occipital) were examined. Sections were stained such patients attending the out-patient clinics each year. In with haematoxylin±eosin, luxol fast blue±cresyl violet and the main, patients coming to autopsy at the UKPDSBRC modi®ed Bielschowsky silver impregnation. On selected enrolled in the programme after contact with promotional regions, immunocytochemistry was performed using the literature circulated through the Parkinson's Disease Society.
biotin±streptavidin method and antibody to ubiquitin (Dako, They then approached either their neurologist, the polyclonal 1 : 150), a-synuclein (gift from Professor B.
UKPDSBRC directly or their GP regarding registering as a Anderton, 1 : 500), tau (Dako, polyclonal 1 : 150) and GFAP prospective donor. A small number of cases of particular (glial ®brillary acidic protein; Dako, polyclonal 1 : 400).
interest were approached in the latter stages of their disease The pathological diagnoses were made using established while attending the NHNN. Some cases in the present series criteria by one neuropathologist (S.E.D.). The diagnosis of have been included in previous publications that included IPD was based on ®nding a clear depletion of brainstem pigmented neurones with Lewy bodies in some of the sonism (Schrag et al., 1999) to a hypothetical sample of 1000 remaining nerve cells and a normal appearance in the cases. This scenario examines predictive performance in an striatum (Oppenheimer, 1984). In cases lacking pathological ideal world where specialists diagnose all parkinsonian cases changes in IPD, diagnoses were established by accepted in the community. Thirdly, using the same population-based neuropathological criteria. PSP was diagnosed according to prevalence data, we contrived a more realistic scenario where NINDS criteria (Hauw et al., 1994). Cases of MSA were we assumed that all new non-IPD cases, being atypical and subdivided into those showing predominantly striatonigral diagnostically more complex, would be referred to an expert involvement, predominant olivopontocerebellar damage or in movement disorders as well as a minority (20%) of new equal involvement of both systems (Quinn, 1994). Cases of IPD for diagnostic con®rmation. This latter ®gure is hypo- vascular parkinsonism were diagnosed when there was thetical, based partially on the experience of NHNN, but is evidence of white matter ischaemic damage in conjunction used mainly for illustrative purposes enabling a sensitivity with ischaemic infarcts within the striatum in the absence of any de®nable pathology known to be responsible for parkinsonism. Corticobasal degeneration (CBD) was diag- nosed according to Revesz and Daniel (1998). A single case of post-encephalitic parkinsonism (PEP) was distinguished by very severe nigral damage with widespread brainstem tangles in a patient with disease onset following an A total of 143 cases (89 male, 54 female) were identi®ed. The encephalitic-like illness when aged 10 years in 1928 and clinical diagnoses were made by 11 neurologists, with ®ve who died aged 81 years. In four cases, other pathological dedicated movement disorder specialists seeing 92% (132).
diagnoses were made according to the neuropathological The mean age of disease onset was 55.5 (range 5±80) years features (Geddes et al., 1993; Jackson and Lowe, 1996; and the mean disease duration was 13 (range 2±71) years (see Morris et al., 1999; O'Sullivan et al., 2000).
Table 1). The mean time from symptom onset to initial clinical diagnosis was 1.6 (range 0±7) years. The clinical diagnosis was later revised in 44 of the 122 cases where full follow-up information was available, after a mean of 3.4 (range 0.5±12) years. The mean duration of disease to ®nal clinical diagnosis in these 44 cases was 5.3 (range 1.5±19) We compared selected clinical features for cases diagnosed as years. The mean time of the last clinical assessment by the IPD or another parkinsonian syndrome using the t-test and c2 treating neurologist prior to death was 2.4 years, with 54% of test for continuous and categorical variables. By cross- patients being seen within the last year of life.
tabulating the clinical and neuropathological diagnoses, the Seventy-three (47 male, 26 female) patients had a ®nal four standard diagnostic parameters were calculated: (i) clinical diagnosis of IPD and 70 (42 male, 28 female) patients sensitivity: the percentage of cases with a particular patho- were diagnosed as having another parkinsonian syndrome logical diagnosis that had been clinically diagnosed correctly (see Table 1). IPD cases were more likely to be older at as having that diagnosis prior to death; (ii) speci®city: the diagnosis, and had a longer disease duration. There was no percentage of cases without a particular pathological diag- difference between time from onset of symptoms to initial nosis that had been clinically diagnosed correctly as not clinical diagnosis, but as almost two-thirds of those with a having that diagnosis prior to death; (iii) positive predictive ®nal clinical diagnosis of another parkinsonian syndrome had value: the percentage of cases which the clinicians had their diagnosis changed, they had longer disease duration at diagnosed correctly with a particular diagnosis which was the time of their ®nal clinical diagnosis. The clinical con®rmed at post-mortem; and (iv) negative predictive value: diagnosis had been revised to IPD in only two cases after 3 the percentage of cases which the clinicians correctly thought did not have a particular diagnosis, that was con®rmed to be The clinical diagnoses in the 70 cases thought to have a correct at post-mortem. As positive and negative predictive parkinsonian syndrome other than IPD (see Table 2) were: values are a function of the prevalence of disease in the MSA (35), PSP (20), CBD (three), vascular parkinsonism population, they will vary for different populations even (three), parkinsonism undetermined (four), PEP (two) and when sensitivity and speci®city remain constant, the latter one case each of pallidopyramidal degeneration (not further two being a function of the diagnostic test or, in this case, the classi®ed), dopa-responsive juvenile parkinsonism and focal clinicians' diagnostic acumen. We therefore calculated the cerebral atrophy with myoclonus (not further classi®ed).
positive and negative predictive values for IPD, MSA and PSP under three scenarios. First, what was observed from the UKPDSBRC sample under study. Secondly, given the unusual nature of this sample and the over-representation of The ®nal neuropathological diagnoses in the 143 cases (see other parkinsonian disorders, we applied prevalence data Tables 2 and 3) were IPD (79), MSA (34), PSP (19), CBD from a recent population-based prevalence study of parkin- (four), vascular parkinsonism (two) and one case each of Table 1 Simple clinical parameters of 143 cases of parkinsonism divided according to clinical diagnostic groupings Hoehn and Yahr stage at initial diagnosis Cases where clinical diagnosis was revised² ²Information available on 122 cases regarding the timing of both initial and ®nal clinical diagnoses; *P < 0.05, for comparison of cases with a ®nal clinical diagnosis of IPD and another parkinsonian syndrome.
PEP, frontotemporal dementia (without distinctive histol- Of the four cases with pathological CBD, only one was ogy), tauopathy (not otherwise speci®ed), neuronal intra- clinically diagnosed as CBD. One was clinically diagnosed as having vascular parkinsonism, one PSP and one clinically labelled as having focal cerebral atrophy with myoclonus (not further classi®ed). Both cases of pathologically established vascular parkinsonism and the one case of PEP had been Only one case diagnosed clinically as IPD was not con®rmed pathologically (see Tables 2 and 3). However, seven cases of Diagnostic parameters for the main clinical pathologically proven IPD had been misdiagnosed as either MSA (four), CBD (one), PEP (one) and `parkinsonism undetermined' (one). The clinical diagnosis of MSA was also Overall, 122 out of 143 cases were clinically diagnosed good, but cases of both IPD (four) and PSP (one) were correctly, giving an overall positive predictive value of 85.3% wrongly included. Similarly, four cases of pathologically (see Table 4). Other than vascular parkinsonism, which was con®rmed MSA had been misdiagnosed as PSP (two) and based on two cases, the clinical diagnosis of IPD showed the `parkinsonism undetermined' (two). Other misdiagnoses for best overall sensitivity (91.1%) and positive predictive value PSP included CBD (one) and one case found to have a (98.6%), followed by MSA and then PSP. The ®gures for tauopathy (not otherwise speci®ed).
CBD and vascular parkinsonism are based on very small Of the three cases clinically diagnosed as CBD, only one numbers. The speci®city for all the major diagnoses was had the pathological changes of CBD, while one had IPD and extremely high (between 95.4 and 98.4%) with little differ- one had frontotemporal dementia (without distinctive histol- ence for any of the groups, indicating that these neurologists ogy). Two of the three cases clinically diagnosed as having were extremely good at correctly ruling out these speci®c vascular parkinsonism had this diagnosis at post-mortem, while the other had CBD. Only one of the two cases diagnosed as PEP ful®lled the neuropathological criteria, whilst the other was pathologically con®rmed as IPD. One Predictive values for clinical diagnoses under case clinically diagnosed as pallidopyramidal degeneration (not otherwise classi®ed) had a chronic brainstem meningo- Table 5 demonstrates how the positive and negative predict- encephalitis (reported in detail elsewhere; Geddes et al., ive values for each of the main three diagnoses vary as the 1993). The case clinically classi®ed as dopa-responsive prevalence of the speci®c diagnosis alters. The most dramatic juvenile parkinsonism had neuronal intranuclear inclusion effect is seen for IPD, which had a negative predictive value disease at post-mortem (also reported in detail elsewhere; of 90% in the UKPDSBRC sample. When applied to a normal O'Sullivan et al., 2000) and the case classi®ed as having focal population sample, where IPD is a priori likely to be the most cerebral atrophy with myoclonus had CBD. Of the four cases likely diagnosis, this propensity to overdiagnose less common with the ®nal diagnostic label of `parkinsonism undeter- causes of parkinsonism amongst pathologically proven IPD mined', two had MSA, one PSP and one IPD.
has an important detrimental effect on the negative predictive Table 2 Pathological diagnoses in 143 cases of parkinsonism divided according to the Chronic brainstem meningoencephalitis* (1) Dopa-responsive juvenile parkinsonism (1) Neuronal intranuclear inclusion disease* (1) Focal cerebral atrophy with myoclonus (1) *Cases described in detail elsewhere (Geddes et al., 1993; O'Sullivan et al., 2000).
value. In absolute terms, however, this would still only result patients with parkinsonism attending the movement disorders in 81 false-negative diagnoses in every 1000 cases. The clinics or admitted to the NHNN over the last 5 years had a relatively good positive predictive values for both MSA and clinical diagnosis of a parkinsonian syndrome other than IPD.
PSP are markedly attenuated in the community sample, where However, comparison of diagnostic subgroups, for example these disorders are far less common. The clinical predictive IPD, with clinic-based descriptive studies (Hoehn and Yahr, value in Table 5, scenario 3, designed to re¯ect a specialist 1967) shows a similar pro®le of initial symptomatology and movement disorder clinic, is much more like that observed clinical course, suggesting that despite the biases, the subgroups may be reasonably representative of those seen in movement disorders clinics. The predictive value of these clinical diagnoses was, as expected, highly sensitive to the prevalence of disease and hence the context within which The present study has considerable advantages over most patients are seen. In a community setting, the positive previously published clinicopathological series. These in- predictive values for the less common diseases were far clude the detail of clinical documentation and ancillary worse, whilst for IPD there was a deterioration in the negative investigation, the consistency of neuropathological evaluation predictive value. It is likely that a specialist seeing patients in and the independence and impartiality of data acquisition. The an outreach clinic based in primary care would quickly adjust NHNN is a tertiary referral centre, and diagnostic conun- to the different patient patterns and may subsequently alter drums, atypical presentations and unusual cases are seen more their threshold for diagnosing rarer causes of parkinsonism.
frequently than in general hospitals or even regional neuro- Primary care patients are also seen much earlier in the natural logical centres. This leads to a disproportionate bias in the history of the disease and hence cases of MSA and PSP may frequency of atypical parkinsonian syndromes in the clinics.
not have such well developed atypical features to facilitate Furthermore, patients who are undiagnosed or more severely affected and die in hospitals or nursing homes are more likely We found a gratifyingly high accuracy for the diagnosis of to have an autopsy. That almost 50% of the cases included in IPD amongst movement disorder specialists. At 98.6%, the this study were clinically thought to have a cause for positive predictive value for a diagnosis of IPD is certainly parkinsonism other than IPD suggests that the cohort is not higher than previously published data. The only other single representative of patients seen in clinics with a particular centre clinicopathological study of parkinsonism was pub- interest in movement disorders. Approximately one in four lished a decade ago and found an accuracy for clinical Table 3 Clinical diagnoses in 143 cases of parkinsonism divided according to the pathological diagnosisPathological diagnosis Focal cerebral atrophy with myoclonus (1) Neuronal intranuclear inclusion disease (1) Dopa-responsive juvenile parkinsonism (1) Chronic brainstem meningoencephalitis (1) Pallidopyramidal degenerationÐnot otherwise Frontotemporal dementiaÐwithout distinctive diagnosis of IPD of only 76% (Rajput et al., 1991). A year (9%) suggest a broader clinical picture of disease than later, a clinicopathological series from the UKPDSBRC formerly recognized. Alternatively, there may have been a found an identical diagnostic accuracy in cases collected from tendency amongst the clinicians to place too much import- all over the UK (Hughes et al., 1992). In a subsequent interim ance on subtle atypical clinical features for IPD and series, the diagnostic accuracy had increased to 84% overdiagnose less common parkinsonian syndromes. This is (Ansorge et al., 1997), while in a more recent study it perhaps not unreasonable when they work in a hospital setting reached 90% (Hughes et al., 2001). Although the majority of where the probability of such disorders is relatively high.
diagnoses in this most recent series were made by neurolo- While the false-positive rate for the diagnosis of IPD has gists, 14% of cases were diagnosed by general physicians or fallen over the last decade, there is less information regarding geriatricians (Hughes et al., 2001). That study also evaluated false-negative cases. One clinicopathological series found several sets of diagnostic criteria which were unable to that 10% of cases with pathologically proven IPD died with improve this diagnostic accuracy signi®cantly. Although this an alternative clinical diagnosis (Hughes et al., 1993). The ®nding suggested that a clinical diagnostic accuracy of 90% retrospective application of accepted clinical diagnostic may approximate the maximum that can be expected, our criteria to that series suggested that 12% had clinical features ®ndings suggest that specialists in movement disorders may atypical for the accepted clinical spectrum of IPD. These exceed this. However, in the clinicopathological study of included early severe dementia, no apparent response to an Litvan et al. (1998), experts in movement disorders correctly adequate trial of levodopa, early ¯uctuating confusional diagnosed only 77.4% of cases of Lewy body disease states, myoclonus, apraxia, onset of parkinsonism while (including both IPD and DLB) when retrospectively review- taking neuroleptic medication, presence of focal dystonia, ing clinical vignettes of cases compiled from information early marked autonomic dysfunction, onset following sig- gathered at the last clinical assessment prior to death. In that ni®cant head trauma and a stuttering course suggestive of study, the lack of direct patient contact and the proportion of vascular events. Half of those cases had a pathological cases included with parkinsonian syndromes other than IPD process in addition to IPD that may have explained the may have adversely affected the diagnostic accuracy. The atypical clinical appearance: signi®cant plaque and neuro- diagnostic accuracy by the primary treating neurologists for ®brillary tangle deposition, dense cortical Lewy bodies and striatal infarction. This still left 6% of pathologically proven Although we found the sensitivity for a clinical diagnosis IPD cases without additional contaminating pathology with of IPD to be high at 91.1%, the seven false-negative cases clinical features outside the prevailing perceptions for the Table 4 Summary of the diagnostic accuracy for the major parkinsonian syndromes in 143 cases of parkinsonism that came to neuropathological examination over a 10-year periodDiagnosis See text for de®nitions of positive predictive value, sensitivity and speci®city. Limited conclusions can be drawn from the small number of cases with CBD and vascular parkinsonism. *For the purpose of analysis, a ®nal clinical diagnosis of parkinsonism undetermined was considered an incorrect diagnosis.
months prior to the onset of symptoms. Otherwise this case Table 5 Positive and negative predictive values of a had long duration disease with a clinical course typical for diagnosis of IPD, MSA and PSP under various scenarios IPD. This leaves ®ve cases (6%) with pathologically proven brainstem Lewy body IPD having clinical features outside the commonly accepted clinical spectrum. The atypical features seen in these cases include poor levodopa response (four), early autonomic impairment (four), early falls (four), dis- proportionate antecollis (four), denervation on sphincter EMG (one) and prolonged isolated gait freezing before the development of parkinsonism and dementia (one).
The problems associated with the diagnostic label of DLB in this series have already been described. Probably because of referral bias towards patients with a dominant parkinsonian motor syndrome in this movement disorder service, this situation was not common. There were only two cases where 1 = Sample in the present study, diagnosed by neurologists early cognitive decline (occurring within 12 months of the associated with the movement disorders service at the NHNN and onset of parkinsonism) in patients already diagnosed as coming to autopsy at the UKPDSBRC over a 10-year period.
having IPD, was clinically felt to be due to DLB and who 2 = Prevalence of conditions in the population sample, assuming movement disorder specialists diagnose all parkinsonian cases in subsequently satis®ed the pathological criteria for this entity (McKeith et al., 1996, 1999). There were a further 12 cases 3 = Assuming all atypical cases of parkinsonism and 20% of IPD with moderate numbers of cortical Lewy bodies who either cases referred to specialist neurologists associated with a had no cognitive impairment in life or who ®rst developed movement disorder service. PPV = positive predictive value; cognitive dysfunction after a disease course of 10 years or more. Those cases with dementia had a clinical diagnosis of IPD with dementia. As with previous series (Hughes et al., 1992), small numbers of cortical Lewy bodies were identi®ed syndrome of IPD. An even higher false-negative rate was in the vast majority of cases of pathologically con®rmed IPD.
seen in another clinicopathological study (Litvan et al., 1998) Over the last decade, a number of clinical and clinico- where the sensitivity for the diagnosis of Lewy body disease pathological series have clari®ed the clinical features of MSA (including both IPD and DLB) and for IPD alone was 67.2 and PSP, the two conditions most commonly misdiagnosed as and 80%, respectively. Of the seven false-negative cases in IPD (de Bruin and Lees, 1994; Litvan et al., 1996a; Wenning the present series, no alternative neuropathological cause for et al., 1997, 2000). Increased awareness of these features and the atypical clinical features could be found in six. The their clinical overlap with IPD is likely to be responsible for seventh case had dense cortical Lewy body deposition but a the improvement in the diagnostic accuracy of IPD and has clinical history somewhat atypical for DLB, with parkinson- led to a re®nement of the clinical diagnostic criteria for both ism preceding the onset of cognitive impairment by 10 years MSA and PSP (Litvan et al., 1996b; Gilman et al., 1999).
with associated autonomic impairment, corticospinal tract Nevertheless, the accuracy of clinical diagnosis of the other dysfunction, supranuclear gaze palsy and myoclonus. One of common neurodegenerative parkinsonian syndromes was less the remaining six cases was diagnosed clinically as probably than with IPD. However, the positive predictive value and having PEP, because of a history of an encephalitic illness 6 sensitivity for a diagnosis of both MSA and PSP in the present study were higher than most previous prospective clinico- seen in some earlier studies and is re¯ected in the number of pathological series and studies using the retrospective different sets of diagnostic criteria which have been proposed application of clinical diagnostic criteria (Litvan et al., (Litvan et al., 1996c). In the present study, the sensitivity for 1996a, c, 1997a; Wenning et al., 2000).
the diagnosis of PSP was 84.2%. The most recently proposed The situation with MSA is made dif®cult by the 10±20% of clinical diagnostic criteria for PSP have been validated cases who have relatively pure parkinsonism which may be retrospectively in a data set of cases with pathologically characterized by features previously thought to be more established parkinsonian syndromes (Litvan et al, 1996b).
typical of IPD, including asymmetry, levodopa responsive- They appear relatively restrictive, with sensitivities of 83 and ness and the development of levodopa-induced dyskinesias 50% for a diagnosis of possible and probable PSP, respect- and motor ¯uctuations (Wenning et al., 1994, 1997, 2000).
ively, although they await further validation.
Two studies comparing the clinical features of pathologically Although the number of cases with CBD was very small in proven MSA and IPD (Litvan et al., 1997a; Wenning et al., the present study, it is of note that both the positive predictive 2000) have pointed to preserved cognition and the absence of value and sensitivity were poor. Only one of the three cases neuropsychiatric toxicity as previously unrecognized features clinically diagnosed was con®rmed pathologically, and only more suggestive of MSA than IPD. We have found that one of the four cases found at post-mortem was clinically neurologists specializing in movement disorders were correct diagnosed in life. The clinical and pathological heterogeneity in 85.7% of cases clinically diagnosed with MSA, equating to of CBD is now well recognized (Rinne et al., 1994; Wenning a false-positive rate of 14.3%. The false-positive rate in MSA et al., 1998; Kertesz et al., 2000). A proportion of cases with has received relatively little attention to date, although in one CBD may not be seen by movement disorder specialists at all, cohort retrospectively analysed by movement disorder spe- coming under the care of psychiatrists, dementia specialists or cialists it approximated 20% (Litvan et al., 1997a).
psycho-geriatricians. Previous larger series have varied In the present study, we found the sensitivity for a considerably in the accuracy of clinical diagnosis of CBD, diagnosis of MSA to be 88.2%, with 30 of the 34 cases of with between 53 and 94% of clinically diagnosed cases pathologically proven MSA being diagnosed correctly. In one having the disease at post-mortem and ~50% of pathologic- of the largest clinicopathological studies of MSA (Wenning ally established cases being diagnosed correctly in life et al., 1995), a third of 35 pathologically proven cases carried (Litvan et al., 1997b; Wenning et al., 1998; Boeve et al., another clinical diagnosis, usually IPD, at the time of death.
Subanalysis of those cases suggested that the diagnostic More than 60% of cases with the ®nal clinical diagnosis of accuracy was far higher amongst cases seen by neurologists a parkinsonian syndrome other than IPD had their diagnosis specializing in movement disorders (seven of the patients in changed during the course of their illness. Of these, 60% were that series were also included in the present series). Similarly, changed from an initial clinical diagnosis of IPD. This is in another series (Litvan et al., 1997a), only 50% of cases similar to previous clinicopathological studies where clinical with pathologically proven MSA had been diagnosed information is available regarding the temporal dynamics of correctly by their primary neurologist, while retrospective changes in the clinical diagnosis between the ®rst and last analysis by neurologists specializing in movement disorders clinical assessments (Litvan et al., 1996a, 1997a; Wenning improved this sensitivity to ~70%. Several studies have et al., 1998). Revision of the clinical diagnosis occurred after compared the clinical features of pathologically proven MSA a mean of 5.4 years of disease, but in several cases it occurred with IPD and developed scoring systems weighted for well into the second decade of ill-health.
different clinical features (Colosimo et al., 1995; Wenning The present study has shown a high degree of diagnostic et al., 2000). These have produced sensitivities of ~90%. The accuracy for IPD, MSA and PSP amongst neurologists application of these scoring systems in new independent specializing in movement disorders. Many previous series clinical series is likely to be less impressive as they are assessing diagnostic accuracy have used retrospective internally derived and therefore overestimate their true methods relying on abstracted clinical information developed into arti®cial clinical vignettes then assessed by specialists We found an 80% accuracy for the clinical diagnosis of who have had no contact with the patient. This methodology PSP in the present series. There is little available comparative potentially allows certain subtle, but diagnostically valuable, literature, but there are case reports of patients with patho- clinical information to be highlighted in the vignette, logically established MSA, DLB, CBD and diffuse sub- increasing the chances of an accurate diagnosis, while on cortical gliosis being clinically diagnosed as having PSP the other hand it depends heavily on the reliability and (Fearnley et al., 1991; Wenning et al., 1998). The clinical completeness of the supplied clinical picture by the partici- heterogeneity of PSP, with cases lacking a supranuclear gaze pating neurological centre. We believe our ®ndings re¯ect the palsy, presenting as an isolated akinetic±rigid syndrome or as reality of diagnostic accuracy amongst experienced fully a pure progressive dementing syndrome, has been delineated trained neurologists specializing in movement disorders. We more clearly over the last decade (Daniel et al., 1995; Litvan have not sought to describe in detail the clinical features of et al., 1996a; Verny et al., 1996). This dif®culty in clinical the cases nor to apply available consensus diagnostic criteria, diagnosis is likely to be responsible for the reduced sensitivity merely to report the observed diagnostic accuracy in the light of the available literature. The cohort of cases studied is Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical clearly a small subgroup of patients with parkinsonism who diagnosis of idiopathic Parkinson's disease: a clinico-pathological were seen over the 10-year study period, and has many of the study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55: 181±4.
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supranuclear palsy and multiple system atrophy: a cross-sectional Received July 23, 2001. Revised October 25, 2001.
Verny M, Jellinger KA, Hauw JJ, Bancher C, Litvan I, Agid Y.

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